In the first phase, the candidate will spend one year full time learning the methods of recombinant DNa technology through a program of supervised research and didactic training under the direction of an experienced molecular biologist. The supervised research will involve the study of a female-specific P450 isoenzyme which is known to be developmentally regulated. This isoenzyme, as well as other sexually dimorphic, developmentally regulated P450's has been purified and antibodies are available for screening cDNA clones. In the second phase the candidate will continue her didactic training, but will apply the methods of molecular biology to the study, in animals, of the moleculr mechanisms involved in the regulation of 1) antipsychotic drug-induced dopamine, DA, D2 receptor supersensitivity and 2) turnover of the normal complement of D2 receptors. The goals of the neurobiological studies of D2 receptor sensitivity regulation are: 1) to prepare a cDNA library corresponding to rat striatal mRNAs that may be specifically involved in neuroleptic induced D2 receptor sensitivity and 2) to prepare a cDNA library corresponding to rat striatal mRNAs involve in the turnover of the normal complement of D2 receptors. In order to accoiiplish these goals, selected cDNAs will be prepared using differential (subtractive) hybridization techniqus for cloning, and labeled cDNA probes isolated in the same way. With the labeled cDNa probes it may be possible to detect specific cDNA clones corresponding to specific mRNAs induced by antipsychotic drugs which are not or are only minimally expressed in appropriate controls, one of which is an ontogenic model where rats exposed to haloperidol prenatally are unable to express biochemical evidence of D2 receptor supersensitivity when trated again with haloperidol in adulthood. We now know that the DAergic system has an adaptive capacity, i.e. the ability to alter its sensitivity by up and downregulation of receptor number. Inasmuch as the DAergic system is important in mediating the action of antipsychotic drugs, understanding the molecular mechanisms in the regulation of this adaptive system could have important implications in the treatment of mental illness, in particular in the development of better, less aversive drugs for treatment of schizophrenia, a major goal of mental health research.